Official Title
Signal TrAnsduction Pathway Activity Analysis in OVarian cancER
Phase
Phase 3Lead Sponsor
Gynecological Oncology Center South (GOCZ)Study Type
InterventionalStatus
RecruitingIndication/Condition
Therapy-Associated Cancer Ovarian Neoplasms ...Intervention/Treatment
itraconazole ...Study Participants
148The purpose of this prospective, parallel-group, cohort study is to implement phenotype-guided targeted therapy based on functional signal transduction pathway (STP) activity in recurrent ovarian cancer patients using a novel mRNA-based assay. Existing targeted drugs with tolerable toxicity profiles are used to investigate the therapeutic value beyond their approved indication, which are deemed beneficial in the select group of patients with a relevant predominantly active functional STP, in order to improve survival and maintain quality of life.
Rationale: Ovarian cancer is one of the most lethal cancers in the world. Standard therapy consists of debulking surgery and chemotherapy. However, despite this aggressive treatment, recurrent disease almost invariably occurs resulting in a five-year survival rate of approximately 30%. Tumour growth is driven by several signal transduction pathways (STPs), and twelve major STPs have been identified as important for carcinogenesis. Currently, several targeted therapy drugs are available and new targeted drugs are being developed. With a newly developed technique, Signal Transduction Activation (STA) analysis, it is possible to assess which pathway is predominant in a specific (ovarian) cancer sample. Therefore, we hypothesize that specifically targeting the predominant STP might impair tumour growth and improve survival.
Objective: This study aims to investigate the progression-free survival (PFS) according to RECIST 1.1 criteria on matched targeted therapy by STA-analysis (PFS2) in comparison to the PFS recorded on the therapy administered immediately prior to enrolment (PFS1) in women with recurrent ovarian cancer.
Study design: A multi-centre prospective, parallel-group, cohort study. Study population: Recurrent ovarian cancer patients with platinum-resistant disease, patients who refrain from standard therapy and patients who are not yet eligible for standard palliative chemotherapy, including all histological subtypes.
Intervention: STA-analysis will be performed on a biopsy taken from the recurrent tumour. Patients will be included if a predominant pathway is identified for which a matched targeted drug is available and deemed adequate by the multidisciplinary tumour board. We will start with targeted therapy in patients with oestrogen receptor, androgen receptor, phosphoinositide 3-kinase and Hedgehog pathway active tumours, since targeted therapy interceding these pathways are easily available with tolerable side effects.
Main study parameters/endpoints: The primary outcome is therapy response defined as PFS2/PFS1 ratio according to RECIST 1.1 criteria. Secondary outcomes include the proportion of patients with an actionable active pathway and the proportion of patients receiving matched targeted therapy, best overall response (according to RECIST 1.1 criteria), one-year survival, overall survival, predictive value of STA-analysis results, side effects, quality of life, cost-effectiveness and change in STP activity score comparing the score before treatment and after disease progression.
Letrozole 2.5mg tablet - 2.5mg once dailty until progression of disease.
Bicalutatmide 150mg tablet - 150mg once daily until progression of disease.
Everolimus 10mg tablet - 10mg once daily until progression of disease.
Itraconazole 100mg capsule - 300mg twice daily until progression of disease.
In case of an aberrantly active Estrogen Receptor (ER) pathway, patients will be treated with Letrozole 2.5mg daily orally until progression of disease.
In case of an aberrantly active androgen receptor (AR) pathway, patients will be treated with Bicalutamide 150mg daily orally until progression of disease.
In case of an aberrantly active phosphoinositide 3-kinase (PI3K) pathway, patients will be treated with Everolimus 10mg daily orally until progression of disease.
In case of an aberrantly active Hedgehog (HH) or PI3K pathway, patients will be treated with Itraconazole 300mg twice daily orally until progression of disease.
Inclusion Criteria: Female, age > 18 years Patients with recurrent ovarian cancer who meet one of the following criteria: Platinum-resistant disease, defined as disease recurrence or progression within six months of last platinum-based chemotherapy or; Patient refrains from standard therapy or; Asymptomatic patient who is not yet eligible for standard palliative chemotherapy but has an increase of CA125 tumour marker at two consecutive time points 28 days apart with a value of two times nadir above 35 U/ml. Progressive disease after at least one prior line of systemic treatment for recurrent disease. Radiologically evaluable disease according to RECIST 1.1 criteria (36). Ability and willingness to obtain a tumour biopsy after the last course of standard treatment and before start of the study. Ability and willingness to provide written and oral consent. Able to speak and understand the Dutch language. WHO performance status 0-II. Adequate renal and liver function to start matched targeted therapy (according to the local clinician). Adequate use of contraceptives in case of patients with childbearing potential. Exclusion Criteria: Age < 18 years. Patient is receiving any other anti-cancer therapy (e.g. cytotoxic or targeted drug or radiation) or is chemotherapy naïve. The required wash out period prior to start of matched targeted therapy is at least three weeks. Patient is diagnosed with or treated for a second primary tumour (except non-melanoma skin tumour) one year prior to study inclusion. Inability to obtain (sufficient) tumour material. Previous use of the selected targeted drug as anti-cancer agent. Physical condition WHO III-IV. Pregnant or lactating women. Simultaneous participation in another treatment-related clinical trial. Patients with any other clinically significant medical condition which, in the opinion of the local clinician, makes it undesirable for the patient to participate in this study or which could jeopardize compliance with study requirements including, but not limited to: ongoing or active infection, severe psychiatric illness, or complicated social situations.
